Search for specific inhibitors of multidrug resistance in cancer.
This paper deals with the theoretical background, methods and clinical significance of the search for specific inhibitors of multidrug resistance (MDR) in cancer. After discussing the basic features of the drug pump membrane proteins (MDR1 and MRP) responsible for this phenomenon, the possible mechanism of action of MDR inhibitors is reviewed. Modulators of drug pump expression may include inhibitors of the transcription and translation, as well as the processing and post-translational modifications of MDR1 and MRP. The function of the drug pumps can be effectively inhibited by substrate analogs, inhibitors of ATP-binding and utilization, specific monoclonal antibodies, and by various agents with still non-specified mechanisms. Basic methods are presented for the in vitro screening of MDR inhibitors in whole cells and in pump protein preparations, as well as for the in vivo assessment of the efficiency and safety of such inhibitors. The review also discusses some current problems and perspectives of MDR modulation in clinical tumor therapy.
Sarkadi
B
B
National Institute of Haematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Hungary.
Müller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D027425:ATP-Binding Cassette, Sub-Family C Proteins